PD-L1协同人胎盘间充质干细胞诱导T细胞免疫耐受减轻GVHD机制研究

移植物中T细胞活化增殖诱发的移植物抗宿主病（GVHD）是异基因造血干细胞移植成功的主要障碍。诱导T细胞耐受是克服GVHD发生的关键。项目拟在发现人胎盘间充质干细胞（HPMSCs）通过其表达的PD-L1分子增强对T细胞抑制作用的基础上，通过体内外实验证明PD-L1在HPMSCs上表达可通过改变GVHD患者T细胞TCRCDR3特性，调节Treg功能及细胞因子分泌等方式协同HPMSCs抑制T细胞应答。分析IFN-γ、TNF-α及IL-1β调节PD-L1在HPMSCs上表达的信号通路及其对HPMSCs抑制T细胞增殖的调节作用。并在已发现PD-L1可调节HPMSCs沿SDF-1α/CXCR4轴向迁移的基础上，证明PD-L1可调节HPMSCs在GVHD模型体内的分布及其对GVHD的防治效果。结果将揭示PD-L1协同HPMSCs诱导T细胞耐受的细胞与分子机制，推进HPMSCs治疗GVHD的临床应用进程。

The major obstacle to allogeneic hematopoietic stem cell transplantation is the occurrence of acute graft versus host disease (GVHD) induced by activated T cells from graft. To induce T cell immune tolerance is significance for overcoming GVHD. We have found that PD-L1 expressed in human placenta derived mesenchymal stem cells (HPMSCs) played a key role in the immunosuppressive effects of HPMSCs on T cells. In this research we will focus on, in vitro and in vivo, whether PD-L1 expressed in HPMSCs will promote the inhibitory effects of HPMSCs on the response of T cells, which were from GVHD patients and healthy donors, by changing the property of T cell TCRCDR3 and regulating the differentiation of regulatory T cells and the secretion of some soluble cytokins, et al. The signal regulatory mechanism of IFN-γ, TNF-α and IL-1β up regulating the expression of PD-L1 in HPMSCs and promoting inhibitory effects of HPMSCs on T cells will also be explored in this study. Previously, we have found that PD-L1 could adjust the capacity of HPMSCs along SDF-1α/CXCR4 axial migration. Here, the possible mechanism of PD-L1 regulating the distribution of HPMSCs in the GVHD model mice as well as the preventing effects of HPMSCs on GVHD will be investigated. All the results in this research will demonstrate the role, specially related to PD-1/PD-L1 signal pathway, of HPMSCs in controlling GVHD and reveal the molecular and cellular mechanism of HPMSCs mediating T cell immune tolerance, which will enhance the process of HPMSCs in clinical application.